Tamera J. Corte

Interstitial Lung Disease in Systemic Sclerosis A Simple Staging System

RATIONALE In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. OBJECTIVES To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. METHODS The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. MEASUREMENTS AND MAIN RESULTS Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). CONCLUSIONS An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.

An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort. The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity. The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features. A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort. ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features http://ow.ly/O7qao

Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report

Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.

Significance of connective tissue disease features in idiopathic interstitial pneumonia

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979–2005) were studied (nonspecific interstitial pneumonia (NSIP), n=45; idiopathic pulmonary fibrosis, n=56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21–33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud’s phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14–0.85; p=0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

Detection of Pulmonary Hypertension with Multidetector CT and Echocardiography Alone and in Combination

PURPOSE To test the reliability of potentially new computed tomographic (CT) indicators of pulmonary hypertension (PH) and to establish whether a combination of CT and echocardiographic measurements was more predictive of PH than either test alone. MATERIALS AND METHODS The institutional review board approved this retrospective study; patient consent was not required. Seventy-seven patients undergoing right-sided heart catheterization were examined. CT diameters of the main pulmonary artery, ascending aorta, and thoracic vertebra and cross-sectional area of the main pulmonary artery were measured. Segmental and subsegmental arterial diameters were recorded, and segmental artery size was compared with adjacent bronchus size by using a semiquantitative scoring system. The relationship between CT measurements and mean pulmonary arterial pressure (mPAP) was tested with linear regression. Multivariate regression was used to establish a composite index of mPAP by using CT markers of PH with echocardiography-derived right ventricular systolic pressure (RVSP). Post hoc logistic regression and receiver operating characteristic curve analysis were performed to test the diagnostic ability of the CT-echocardiography composite. RESULTS The ratios of the diameter of the main pulmonary artery to the diameter of the ascending aorta (R(2) = 0.45; P < .001) and of the cross-sectional area of the pulmonary artery to the diameter of the ascending aorta (R(2) = 0.45; P < .001) correlated equally with mPAP. The ratio of the diameter of the main pulmonary artery to the diameter of the thoracic vertebra, the segmental arterial diameter, and the segmental artery-to-bronchus ratio were related to mPAP but did not strengthen correlations compared with the ratio of the diameter of the main pulmonary artery to the diameter of the ascending aorta alone. A composite index of the ratio of the diameter of the main pulmonary artery to the diameter of the ascending aorta and echocardiography-derived RVSP was more strongly related (R(2) = 0.55) to mPAP and was more significantly predictive of PH than either measure alone. CONCLUSION A combination of CT and echocardiographic markers of PH is more closely related to mPAP than either test in isolation.

The Effect of Diffuse Pulmonary Fibrosis on the Reliability of CT Signs of Pulmonary Hypertension

PURPOSE To determine whether pulmonary artery (PA) dilatation is a reliable indicator of pulmonary hypertension (PH) in patients with pulmonary fibrosis. MATERIALS AND METHODS This study had institutional review board approval. Patient consent was not required. Seventy-seven patients (39 men, 38 women) who underwent right heart catheterization were studied. The study population was divided into 30 patients with pulmonary fibrosis (group A), and 47 without (group B). The main PA diameter (dPA) and ascending aorta diameter (dAA) were measured by using computed tomography (CT), and the extent of fibrosis was recorded in group A. The dPA and the dPA/dAA ratio were correlated (Spearman rank) with mean PA pressure (mPAP) and pulmonary vascular resistance index (PVRi). The relationship between dPA and pulmonary fibrosis extent and total lung capacity (TLC) was examined by using multivariate linear regression. RESULTS There were strong correlations between dPA and both mPAP (r = 0.67, P < .0001) and PVRi (r = 0.78, P < .0001) in group B. In contrast, there were no significant correlations in group A (r = 0.23, P = .22 for mPAP and r = 0.23, P = .28 for PVRi). The dPA/dAA ratio had similar relationships to dPA alone in group B (r = 0.72, P < .0001 for mPAP and r = 0.71, P < .0001 for PVRi), but significantly strengthened the correlations in group A (r = 0.54, P < .005 for mPAP and r = 0.48, P = .04 for PVRi). PA dilatation occurred in group A in the absence of significant PH, and was unrelated to CT fibrosis score or TLC. CONCLUSION PA dilatation occurs in the absence of PH in patients with pulmonary fibrosis and is therefore an unreliable sign of PH in these patients.

Pulmonary Vascular Resistance Predicts Early Mortality in Patients with Diffuse Fibrotic Lung Disease and Suspected Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is associated with a poor prognosis in diffuse lung disease (DLD). A study was undertaken to compare the prognostic significance of invasive and non-invasive parameters in patients with DLD and suspected PH. Methods: Hospital records of consecutive patients with DLD undergoing right heart catheterisation (RHC) were reviewed (n = 66). Mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and non-invasive variables were examined against early (within 12 months) and overall mortality. A priori thresholds were examined against early mortality. Relationships between mPAP, PVR and non-invasive markers were assessed. Results: Fifty patients had PH on RHC (mean (SD) mPAP 33.5 (11.8) mm Hg, PVR 5.9 (4.3) Wood units (WU)). Raised PVR was strongly associated with early mortality (odds ratio (OR) 1.30; 95% confidence interval (CI) 1.11 to 1.52; p = 0.001), with PVR ⩾6.23 WU being the optimal threshold after adjustment for age, gender, composite physiological index (CPI) and diagnosis of idiopathic pulmonary fibrosis (OR 11.09; 95% CI 2.54 to 48.36; p = 0.001). Early mortality was linked, albeit less strongly, to right ventricular dilation at echocardiography, but not to other non-invasive variables or mPAP. Overall mortality was most strongly associated with increasing CPI levels. Correlations between PVR and non-invasive variables were moderate (R2 <0.32), improving little following construction of a multivariate index which did not itself predict mortality. Conclusion: In severe DLD, early mortality is strongly linked to increased PVR but not to other RHC or non-invasive variables. These findings suggest that the threshold for RHC in severe DLD should be low, enabling prioritisation of aggressive treatment including lung transplantation.

Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease

OBJECTIVES In a multi-centre study, we sought to determine whether extent of disease on high-resolution CT (HRCT) lung, reported using a simple grading system, is predictive of decline and mortality in SSc-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables. METHODS SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All HRCTs and PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease: >20%: extensive; <20%: limited; unclear: indeterminate. Indeterminate HRCTs were converted to limited or extensive using a forced vital capacity threshold of 70%. The composite outcome variable was deterioration (need for home oxygen or lung transplantation), or death. RESULTS Among 172 patients followed for mean (s.d.) of 3.5 (2.9) years, there were 30 outcome events. In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) = 3.0, 95% CI 1.2, 7.5 and P = 0.02. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in 172 patients), serial diffusing capacity of the lung for carbon monoxide by alveolar volume ratio (ml/min/mmHg/l) (aHR = 0.4; 95% CI 0.3, 0.7; P = 0.001) and forced vital capacity (dl) (aHR = 0.9; 95% CI 0.8, 0.97; P = 0.008), were also strongly predictive of outcome. CONCLUSION Extensive disease (>20%) on HRCT at baseline, reported using a semi-quantitative grading system, is associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited disease. Serial PFTs are informative in follow-up of patients.

Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia.

RATIONALE Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. OBJECTIVES To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. METHODS In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. MEASUREMENTS AND MAIN RESULTS Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m(2) and reduced cardiac index of 2.21 (± 0.5) L/min/m(2) were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). CONCLUSIONS This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

Pulmonary hypertension in sarcoidosis: A review

Pulmonary hypertension (PH) is a well‐recognized complication of sarcoidosis. Patients with sarcoidosis‐associated PH (SAPH) have poorer functional status and greater supplemental oxygen requirements than sarcoidosis patients without PH, and are more likely to be listed for lung transplantation. PH is an independent risk factor for mortality in sarcoidosis patients awaiting lung transplantation. The pathophysiology of SAPH is complex, with multiple mechanisms contributing to pathogenesis, including the fibrous destruction of the pulmonary vascular bed, extrinsic compression of the central pulmonary vessels and an intrinsic vasculopathy. Recognition of SAPH may be delayed as it can be masked by the clinical picture of underlying pulmonary sarcoidosis, and right heart catheter remains the gold‐standard for diagnosis. Management of SAPH is based on reversal of resting hypoxaemia, treatment of comorbidities and treatment of the underlying sarcoidosis. The use of corticosteroids in SAPH is controversial. Specific PH therapy is not routinely recommended in SAPH as there are no successful placebo‐controlled trials, although there is limited data to suggest that endothelin receptor antagonists and phosphodiesterase‐5 inhibitors may be useful.